Project Summary The goal of R01DA013324 renewal is to investigate the host genetic basis for hepatitis B virus (HBV) recovery in persons living with and without HIV. HBV Infection results in either a successful immune response and recovery or a chronic infection. Anti-viral drugs control HBV replication but cannot cure chronic hepatitis B (CHB). Moreover, lifelong therapy is unsustainable for many, which is a major threat to the calls to eliminate HBV by 2030. A cure for HBV is urgently needed. Understanding how HBV infection is naturally controlled in many infected persons may provide lessons for how to produce a ?functional? cure. There is overwhelming evidence that host genetic differences explain why some persons can recover from an HBV infection including family studies, candidate gene studies, and genome wide association studies (GWAS) in Asian populations. However, these prior GWAS excluded European- and African-ancestry populations despite high HBV endemicity in Africa (>6% of the population has CHB). We propose to renew R01013324 to fill in the missing knowledge on host genetic basis for HBV recovery and to extend that work by detailed studies of host and virus. To this end, Aim 1 focuses on discovering novel genetic variants in a panel of African ancestry individuals by comparing single nucleotide polymorphisms (SNP) from existing GWAS data in persons with HBV recovery (N=8667) and with CHB (N=1594). The inclusion of persons living with HIV (PLWH) allows comparisons of mechanisms of recovery based on HIV. Aim 2 follows by performing a trans-ethnic GWAS analysis using the African ancestry panel from Aim 1 along with European ancestry individuals from North America and the UK Biobank and with Chinese ancestry individuals. These GWAS data are available through collaborators and will also include PLWH. Aim 3 focuses on integrating the host genomic data from Aims 1 and 2 with viral genomics to understand the influence of the host immune response on the viral genome. Deep sequencing of HBV will be performed on 759 individuals to determine viral amino acid changes that are associated with host SNPs identified in Aims 1 and 2. A viral-host genomewide interaction analysis will also be performed, and HBV sequence differences will be compared by HIV status.Our group has made multiple important discoveries on the host genetic basis of hepatitis C virus spontaneous clearance. Using our developed expertise, we and our team of international collaborators will apply our methodological approaches to HBV recovery. Because CHB is the leading cause of liver disease and hepatocellular carcinoma and a leading cause of morbidity and mortality in PLWH, discovering a functional cure has important public health implications.